Thrombosis is more than excessive blood clotting; it also involves vascular inflammation. The classic triad of Virchow identifies three major elements in the pathophysiology of thrombosis: endothelial injury, a decrease in blood flow, and an imbalance between procoagulant and anticoagulant factors.
Endothelial cells can be activated or injured by a variety of stimuli, including mechanical trauma, endotoxins and cy-tokines, proteases, inflammatory mediators, immune complex deposition, oxygen radicals, and hypoxia. Each of these stimuli affects multiple facets of endothelial cell function, ultimately changing the cell from its natural antithrombotic state to a pro-thrombotic one.
The vascular endothelium, in its unique location in the vessel wall, is capable of sensing and responding to the different mechanical forces in the blood circulation. The shear stress caused by the friction from blood flow seems to be particularly important in modulating endothelial functions. In areas of linear flow, the blood moves in ordered laminar patterns in a regular pulsatile fashion. Such a steady, laminar blood flow apparently promotes an antithrombotic endothelial phenotype. In areas of disrupted flow, such as at vascular bifurcations or stenoses, the endothelium may be exposed to significant changes in shear gradients, and the cells may become activated and prothrombotic.
Imbalance between procoagulant and anticoagulant factors can be hereditary or acquired [see Table 1]. Some clotting factors, such as factor VIII and fibrinogen, are acute-phase reactants: their plasma levels increase significantly with acute inflammation, possibly conferring a transient prothrombotic state. Some hereditary deficiencies of anticoagulant proteins, such as factor V Leiden and antithrombin (AT), are associated with recurrent thrombosis; these are among the best understood clinical hyper-coagulable states.
Although the hypercoagulable state is systemic, thrombosis occurs locally (e.g., in the lower extremities). The clinical outcome likely reflects a complex interaction between the systemic prothrombotic predisposition and local hemostatic control mechanisms specific to the vascular bed. Specific and distinctive gene transcript expression patterns in different vascular beds have now been demonstrated.1
Assessment of Patients with Thrombotic Disorders
Primary clinical issues in thrombotic disorders
Important questions in the assessment of thrombosis include the following: (1) How likely is it that the thrombosis is caused by an underlying hypercoagulable state? (2) How extensive a workup is indicated? (3) When should the workup be done? Answers to these questions come from a consideration of the patient’s age at the time of the first thrombosis; presence or absence of a provoking factor; family history and past medical history of response to situations associated with high risk of thrombosis; and the site, type, and severity of the thrombosis.
Age of Onset of First Thrombosis
In a retrospective study involving 150 families with an inherited predisposition to recurrent thrombosis (thrombophilia), the mean age at the time of the first thrombosis was 35 to 40 years. However, the first episode of thrombosis can occur as early as the second decade of life if the patient has more than one hereditary risk factor.2
Presence or Absence of a Provoking Factor
Common triggers of thrombosis are surgery, trauma, pregnancy, malignancy, prolonged immobilization, and infection. Malignancy or infection can be clinically overt or subclinical. Those circumstances can provoke thrombosis even in persons with a normal coagulation system, and they often uncover a thrombophilia that had been clinically silent.2 However, sometimes no provoking factors can be identified. Such a spontaneous, idiopathic thrombosis, especially when it occurs in a young person, strongly suggests an underlying hereditary hy-percoagulable state.
If thrombosis develops in a patient who has had previous pregnancies or surgeries (especially orthopedic procedures)without any thrombotic complications, an acquired hypercoagulable state should be considered. Likely conditions in such cases are antiphospholipid antibody syndrome or Trousseau syndrome (see below).
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Table 1 Inherited and Acquired Hypercoagulable States |
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Inherited |
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Resistance to activated protein C/factor V Leiden |
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Prothrombin gene mutation 20210A |
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Antithrombin III deficiency |
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Protein C deficiency |
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Protein S deficiency |
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Hyperhomocysteinemia |
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Acquired |
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Antiphospholipid antibody syndrome |
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Hypercoagulable state associated with physiologic or thrombo-genic stimuli: |
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Advancing age |
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Oral contraceptives |
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Pregnancy |
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Surgery |
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Trauma |
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Hypercoagulable state associated with other clinical conditions: Malignancy—Trousseau syndrome |
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Heparin-induced thrombocytopenia with thrombosis |
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Nephrotic syndrome |
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Hyperviscosity (polycythemia vera, Waldenstrom macroglo-binemia, multiple myeloma) |
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Myeloproliferative disorders (polycythemia vera, essential thrombocythemia) |
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Paroxysmal nocturnal hemoglobinuria |
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Sickle cell anemia |
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Rare or not well established |
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Dysfibrinogenemia |
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Hypoplasminogenemia, dysplasminogenemia |
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Abnormal thrombomodulin |
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Factor XII deficiency |
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Elevated factor VII, factor VIII, fibrinogen, lipoprotein(a), plasminogen activator inhibitor-1 |
Table 2 Screening Tests for Patients with Suspected Hypercoagulable State
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Underlying State |
Laboratory Evaluation |
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Venous thrombosis |
Resistance to activated protein C |
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Factor V Leiden (genetic test) |
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Clotting assay (unnecessary if the genetic test for factor V Leiden is positive) |
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Prothrombin mutation 20210A (genetic test) |
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Antithrombin III (functional assay) |
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Protein C (functional assay) |
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Protein S |
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Functional assay |
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Antigenic assay for free protein S |
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Arterial thrombosis |
Antibodies associated with heparin-induced thrombocytopenia* |
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Chronic disseminated intravascular coagulation (Trousseau syndrome)* |
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Lipoprotein(a) |
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Venous thrombosis and/or arterial thrombosis |
Plasma homocysteine |
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Fasting level |
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Level after methionine loading (if thrombo-philia is strongly suspected) |
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Antiphospholipid antibody |
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Clotting assays for lupuslike anticoagulant |
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ELISA for anticardiolipin antibodies IgG and IgM |
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Dysfibrinogenemia (if thrombophilia is strongly suspected) |
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Functional assay for fibrinogen level |
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Thrombin time, reptilase time |
*In appropriate clinical settings.
ELISA—enzyme-linked immunosorbent assay
Family History
Objectively documented venous thromboembolism before 50 years of age in a first-degree family member strongly suggests a hereditary thrombotic disorder. However, a negative family history does not exclude a hereditary condition. Clinical thrombosis is frequently the culmination of multiple thrombogenic risk factors, only one of which may be hereditary and irreversible. In patients with symptomatic thrombosis and well-documented hereditary hypercoagulable states, it is not uncommon to find other family members with the same deficiency but no clinical thrombosis.
Recurrent Thrombosis
A patient who experiences recurrent thrombosis likely has a hypercoagulable state (hereditary or acquired). However, if a patient who initially presented with deep vein thrombosis (DVT) in a lower extremity returns with symptoms involving the same leg, the problem may be postphlebitic syndrome rather than recurrent thrombosis. Acute exacerbation of the post-phlebitic syndrome, with its increased leg edema and pain, can be difficult to distinguish from recurrent acute DVT. As an anticipatory measure, it is sometimes useful to obtain a repeat compression ultrasound study of the lower extremity after resolution of an acute episode of DVT; the repeat scan can provide a baseline for future comparison.
Site of Thrombosis
Most commonly, thromboses involve the deep veins of the lower extremities. Thrombosis at an atypical site, such as the hepatic, mesenteric, or cerebral veins (or skin necrosis after warfarin administration), increases the likelihood of an underlying hypercoagulable state. Spontaneous axillary vein thrombosis may also indicate the presence of an underlying hypercoagula-ble state, but this association is controversial.
Recurrent thrombosis at arterial sites has a differential diag-nosis—and therefore a workup—that is quite different from that for recurrent venous thrombosis [see Table 2]. Most of the common hereditary hypercoagulable states (e.g., AT deficiency or factor V Leiden) are associated with venous thromboses, such as DVT in the lower extremities. They are seldom associated with arterial thromboses, such as transient ischemic attack, stroke, digital ischemia, and myocardial infarction. A few hypercoagu-lable states, such as the antiphospholipid syndrome and hyper-homocysteinemia, are associated with both types of thrombosis.
The Hypercoagulable Workup
Extent of the workup On the basis of the above clinical considerations, one may estimate the likelihood of an underlying thrombophilia in a given patient with thrombosis [see Table 3]. Because studies of cost-effectiveness and outcomes are not available, it is difficult to list strict practice guidelines regarding the extent of the hypercoagulable workup. In general, however, if the likelihood of an underlying hypercoagulable state is high, an extensive workup is warranted.
A limited workup is appropriate for mild to moderate DVT of the lower extremities with an obvious provoking factor. For example, in a young woman who experiences DVT in the superficial femoral vein while on an oral contraceptive, evaluation of factor V Leiden, prothrombin mutation 20210A, AT, protein C, protein S, homocysteine, anticardiolipin antibodies, and lupus anticoagulant may be sufficient. On the other hand, an acquired hypercoagulable state should be considered in an elderly patient with a spontaneous DVT and no history of previous thrombosis. Diagnostic possibilities in such cases would include antiphos-pholipid antibody syndrome, acquired AT deficiency (if the patient has evidence of nephrotic syndrome), or Trousseau syndrome.
When the clinical history strongly suggests thrombophilia— as in a patient with recurrent thrombosis or thrombosis at atypical sites—one may argue that a workup for an underlying hy-percoagulable state is unnecessary because the result will not alter the management of the case. However, the identification of any underlying risk factors will improve the understanding of the disease for both the patient and the treating physician; and it will guide the counseling of the patient, especially regarding the need for screening of related family members. In the case of hy-perhomocysteinemia and elevated lipoprotein(a) levels, identifi-cation of risk factors will permit the use of specific therapies (see below).
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Table 3 Clinical Features That Suggest Thrombophilia |
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Age at onset of first thrombosis < 50 yr |
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No identifiable risk factor |
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Positive family history |
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Recurrent thrombosis |
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Atypical site of thrombosis |
Timing of the workup The clinician needs to know not only what tests to order but when to order them. In acute thrombosis, many inhibitors of the clotting cascade (e.g., AT and protein C) are consumed. Immediately after the episode, their plasma levels may be decreased, even in patients who do not have a hereditary deficiency. Heparin therapy can reduce antithrombin levels up to 20%, whereas warfarin treatment reduces the levels of protein C and protein S. Usually it is best to postpone measurement of these inhibitors until the acute thrombotic episode is completely resolved, preferably 4 weeks after termination of oral anticoagulation therapy. Tests for specific genotypes (e.g., factor V Leiden) can be performed at any time, however.
Frequency and Relative Risk of Venous Thromboembolism
The frequency of various hypercoagulable states in unselect-ed patients who present with venous thrombosis ranges from 1% to 25% [see Table 4]. It should be recognized that these thrombophilias do not confer equivalent thrombotic risk. Factor V Leiden and prothrombin mutation 20210A, the two most prevalent risk factors, confer only a modest increase in relative risk of thrombosis, approximately threefold to sevenfold above normal. Moderate hyperhomocysteinemia, another common risk factor, also carries a modest increase in risk. Heterozygous deficiencies of AT, protein C, and protein S are generally considered more significant risk factors than factor V Leiden. AT deficiency and the antiphospholipid antibody syndrome are probably the greatest risk factors. The recurrence rate in patients with antiphospholipid antibody syndrome is as high as 50% to 70% in some studies.
Patients with symptomatic thrombosis frequently have more than one risk factor, which may have a synergistic effect in increasing the thrombosis risk. For example, women with factor V Leiden who use oral contraceptives have a risk of venous thromboembolism that is 35-fold higher than that in the general population.
Table 4 Frequency and Relative Risk of Venous Thrombosis in Selected Hypercoagulable States*
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Condition |
Relative Risk |
Frequencyt |
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Antithrombin III deficiency |
High |
1%-2% |
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Protein C deficiency |
High |
3%-4% |
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Protein S deficiency |
High |
2%-3% |
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Factor V Leiden |
Modest |
20%-25% |
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Prothrombin mutation 20210A |
Modest |
10% |
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Hyperhomocysteinemia |
Modest |
10% |
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Oral contraceptive use |
Modest |
NA |
*The incidence of venous thromboembolism in the normal population is estimated to be 0.008% a year (0.03% a year in patients who take oral contraceptives). "Modest risk is defined as an approximate 2.5-fold to fivefold increase in thromboembolism, on the basis of data from the Leiden Thrombophilia Study146; high risk is defined as an approximate threefold to fourfold increase over that for factor V Leiden.2 tin unselected patients with venous thromboembolism.
